The physical and chemical nature of the pathways for macromolecule exchange when the permeability of microvessels is increased remains poorly understood. The specific aims of the proposed research are to investigate three hypotheses which describe the transport mechanisms responsible for increased macromolecule exchange in post-capillary venules. The first hypothesis states that passive diffusive and convective transport through porous pathways are the principal mechanisms whereby water and macromolecules cross the capillary wall during high permeability states. The second hypothesis states that the area for exchange and the length of the pathway for water and solute exchange across microvessels are modulated via changes in the size and shape of endothelial cells in the region of the intercellular junctions. The third hypothesis states that the frictional resistance to water and solute movement through porous intercellular pathways during altered permeability is determined by networks of fibrous molecules associated with the basement membrane and edothelial cell surface. These hypotheses are an extension of the concepts developed during the current funding period. To test the hypotheses the investigators will use methods developed in their laboratory to cannulate and perfuse individual microvessels and to measure the premeability coefficients of their walls to fluorescently labelled macromolecular solutes. An important part of the research plan is to investigate premeability properties in mammalian post- capillary venules. Permeability will be increased in a graded manner using the calcium ionophore A23187 and by using inflammatory mediators. The ultrastructure of microvessels in the segment used to measure permeability will also be examined to correlate structure and function. The investigations provide a direct experimental route to further understanding of the mechanisms which modulate capillary permeability during high permeability states leading to edema.